NcXHF

TARGETING THE PI3K PATHWAY IN HNSCC
Targeting the PI3K Pathway in Head and Neck Squamous
Cell Carcinoma
Pedro Henrique Isaacsson Velho, MD, Gilberto Castro Jr, MD, PhD, and Christine H. Chung, MD
OVERVIEW
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease arising from the mucosal epithelia in the head and neck
region. The most common risk factors are tobacco use, alcohol consumption, and HPV infection, particularly in the oropharynx. The
HPV-positive HNSCC is biologically and clinically distinct from the HPV-negative HNSCC; however, deregulations within the phosphatidylinositol
3-kinase (PI3K) pathway are frequent in both HPV-positive and HPV-negative HNSCC as it is the most frequently altered
oncogenic pathway with a gain-of-function in HNSCC. This article reviews the basic biology and clinical data from the trials involving
anticancer agents targeting the PI3K pathway in HNSCC. It also discusses the difficulties of translating the preclinical data to tangible
clinical efficacy of these agents in patients with HNSCC even when there is significant preclinical data suggesting the PI3K pathway
is a promising therapeutic target in HNSCC. We conclude that additional studies to determine appropriate patient selection for the
activation of PI3K pathway and to develop targeted agents either as a monotherapy or combination therapy with favorable toxicity
profiles are required before a broader clinical application.
Head and neck squamous cell carcinoma is a heterogeneous
disease originating from the mucosal epithelia in
the head and neck region, most commonly the oral cavity,
oropharynx, hypopharynx, and larynx. The risk factors are
tobacco use, alcohol consumption, and HPV infection, particularly
in the oropharynx. 1,2 The HPV-positive HNSCC is
now established as a separate entity with distinct clinical
characteristics, including younger age of onset, better performance
status, less smoking history, and its association with
high-risk sexual behaviors compared to the HPV-negative
HNSCC. 3,4 In addition, the HPV-positive HNSCC has a
distinct molecular profıle compared to the HPV-negative
HNSCC, including lack of TP53 and CDKN2A mutations;
however, mutations or copy number variations of genes
within the PI3K pathway are frequent in both HPV-positive
and HPV-negative HNSCC as it is the most frequently
altered oncogenic pathway with a gain-of-function in
HNSCC. 5 This article reviews the basic biology and clinical
data from trials involving the PI3K pathway inhibitors in patients
with HNSCC.
BASIC BIOLOGY OF THE PI3K PATHWAY
P13Ks are divided into three classes: class I, II, and III. The
differences in these classes are comprehensively reviewed by
Thorpe et al. 6 Class I is further divided into subclass IA and
IB in mammals. Class IA PI3Ks are heterodimeric kinases
consisting of a p110 catalytic subunit (p110-alpha, p110-beta,
and p110-delta encoded by PIK3CA, PIK3CB, and PIK3CD,
respectively) and a p85 regulatory subunit (p85-alpha and its
splice variants, p55-alpha and p50-alpha, encoded by
PIK3R1; p85-beta encoded by PIK3R2; and p55-gamma encoded
by PIK3R3). These three p110 catalytic subunit isoforms
can form a heterodimer with any of the fıve p85
regulatory subunits. Class IB PI3Ks are heterodimeric kinases
consisting of a p110-gamma catalytic subunit encoded
by PIK3CG and a p101 or p87 regulatory subunit encoded by
PIK3R5 and PIK3R6, respectively. Unlike class I PI3Ks, class
II PI3Ks are monomeric lipid kinases without a regulatory
subunit. There are three class II isoforms, including PI3K-
C2-alpha, PIK3-C2-beta, and PIK3-C2-gamma encoded by
PIK3C2A, PIK3C2B, and PIK3C2G, respectively. VPS34 is
the sole Class III PI3K encoded by PIK3C3 and forms a heterodimer
with VPS15 encoded by PIK3R4.
Activation of the PI3K signaling pathway is highly regulated.
PI3K activation is initiated by activated receptor tyrosine
kinases such as ErbB family receptors, fıbroblast
growth factor receptors, insulin-like growth factor 1 receptor
and others, as well as G protein-coupled receptors. 6,7 On activation,
class I PI3Ks translocate to the plasma membrane
where inhibition by the p85 regulatory subunit is relieved,
and the p110 catalytic subunit catalyzes the phosphorylation
From the Department of Clinical Oncology, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil; Department of Oncology and
Department of Head and Neck Surgery-Otolaryngology, The Johns Hopkins Medical Institutions, Baltimore, MD.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Christine H. Chung, MD, Department of Oncology and Department of Head and Neck Surgery-Otolaryngology, Johns Hopkins University School of Medicine, Sidney Kimmel
Comprehensive Cancer Center, 1550 Orleans St. CRB-2 Room 546, Baltimore, MD 21287-0014; email: cchung11@jhmi.edu.
© 2015 by American Society of Clinical Oncology.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK 123